Reduction or prevention of sensitization to drugs

ABSTRACT

The present invention is directed to a method of reducing or preventing skin sensitization by inhibiting the immunological processing of a sensitizing drug as an antigen. The drug is sensitizing to humans, i.e., the drug is susceptible to inducing skin or mucosa sensitization in a human when the drug is transdermally administered to the human at a therapeutically effective rate. Skin sensitization reduction or prevention is induced by coadministering to the skin or mucosa of the human: 
     (a) a therapeutically effective amount of a sensitizing drug, at a therapeutically effective rate over a predetermined period of time; and 
     (b) an antigen processing-inhibiting agent in an amount effective to inhibit the antigen processing of the drug. 
     The system of the invention comprises a matrix adapted to be placed in sensitizing drug and antigen processing-inhibiting agent transmitting relation to the selected skin or mucosa site. The matrix contains sufficient amounts of the drug and the agent to continuously coadminister to the skin or mucosa site the drug, at a therapeutically effective rate and over a predetermined delivery period, and the antigen processing-inhibiting agent, at a rate and for a period of time sufficient to inhibit the processing of the drug as an antigen.

CROSS-REFERENCE TO RELATED APPLICATIONS

This invention is related to the inventions disclosed in the copending,coassigned patent applications Ser. No. 07/217,014 filed on Jul. 8,1988, U.S. Pat. No. 5,000,956 of Amkraut et al., for Prevention ofContact Allergy by Coadministration of a Corticosteroid with aSensitizing Drug; Ser. No. 07/364,932 filed on Jun. 9, 1989 U.S. Pat.No. 5,049,387, of Amkraut, for Inducing Skin Tolerance to a SensitizingNo. 07/549,584 filed on Jul. 6, 1990, of Cormier et al., for Reductionor Prevention of Skin Irritation by Drugs.

FIELD OF THE INVENTION

This invention relates to the transdermal delivery of drugs. Moreparticularly, this invention relates to the reduction or elimination ofsensitization responses caused by the immunological processing ofcertain sensitizing drugs in intracellular vesicles such as thelysosomes.

DESCRIPTION OF TERMS

As used herein, the term "drug" refers to a biologically active agent,compound or composition of matter which is administered for the purposeof providing some beneficial or therapeutic effect.

As used herein, the term "transdermal" delivery or application refers tothe delivery or application of agents by passage through skin, mucosaand/or other body surfaces by topical application or by iontophoresis.

As used herein, the term "therapeutically effective" amount or raterefers to the amount or rate of drug or agent needed to effect thedesired beneficial or therapeutic result.

BACKGROUND OF THE INVENTION

The transdermal route of parenteral drug delivery provides manyadvantages. Unfortunately, however, many drugs which appear to be idealcandidates for transdermal delivery have a tendency to cause undesirableskin reactions, conditions known as contact sensitivity or contactallergy. Therefore, despite the development of the transdermal drugdelivery art, there remains a continuing need for an improved method ofovercoming contact sensitization caused by transdermal delivery of asensitizing drug.

Sensitization is a two-phase process involving distinct biologicalmechanisms of the human immune system. The first phase is called theinduction phase. Induction occurs when the skin of an individual isfirst exposed to the sensitizing drug. In this phase, the sensitizingdrug or antigen is presented to the T lymphocytes (T cells) by theLangerhans cells of the epidermis, either in situ or in the draininglymph node. As a consequence, T cells which recognize the antigenproliferate and to some extent differentiate. Generally, no visible skinreaction is noted during the induction phase. Following induction, someof the individual's lymphocytes are specifically sensitized to the drug.

The second phase of sensitization is called elicitation. Elicitationoccurs when the individual is subsequently (i.e., after induction)exposed to the same sensitizing drug. Elicitation causes a skin reactionto occur. The skin reaction occurring during elicitation is known ascontact dermatitis. During elicitation, the antigen is once againpresented mainly on the Langerhans cells. The T cells, which haveproliferated upon prior exposure to the drug (i.e., during the inductionphase), now come to the treated site and initiate events which result inlocal inflammation or contact dermatitis.

Irritation, on the other hand, is a completely different phenomenon fromcontact (i.e., skin) sensitization. Skin irritation can be caused by avariety of factors including, but not limited to, physical factors(e.g., chafing or occluding the skin in an airtight manner), exposure tocertain chemicals, exposure to pH outside the normal pH range of theskin or mucosa, and bacterial overgrowth. Generally, tissue irritationis the manifested result of damage or toxicity to cells in the skin ormucosa caused by their response to a cytotoxic (i.e., irritating) agent.Sensitization, on the other hand, is the result of a response by theimmune system to an agent (i.e., an antigen) which is not necessarilyirritating.

In general, once the skin has become sensitized, skin reactionsoccurring after re-exposure to the sensitizing agent are difficult toprevent. For this reason, this invention is directed towards preventingsensitization from occurring, as well as reducing or eliminating painand discomfort occurring during the elicitation phase aftersensitization has already been induced.

It is generally accepted that recognition of an antigen by a T cellduring either the induction or the elicitation phase requires that theantigen be associated with a particular molecule (a "class II MHCmolecule") on the surface of an antigen presenting cell (APC). Thisprocess is termed "antigen presentation". Typical APCs are macrophagesand, in the epidermis, Langerhans cells (Friedmann, Curr. Opin.Immunol., 1989, 1:690-693; Aiba et al., Clin. Res., 1990, 38:283A). Forpresentation to occur, the antigen must be converted to an appropriateform for association with the MHC. Events that lead to the associationof an antigen with the cell surface of a class II MHC molecule arecollectively referred to as "antigen processing". Processing involvesthe uptake by an APC of an antigen into acidic intracellular vesiclessuch as the lysosomes where it is exposed to proteases so that theantigen, if it is a large proteintype molecule, is physically orchemically altered (Ziegler et al., Proc. Natl. Acad. Sci. USA 1982,79:175-178). Class II MHC molecules then associate with the antigenicmoiety, intracellularly, whereupon the complex is transported to thesurface membrane of the APC. Only then will the antigen be effectivelyrecognized by the T cells.

The low pH of intracellular vesicles has been shown to be a factor inregulating the formation of functional antigen/class II MHC complexes.Ziegler et al. (ibid.) have found that by using lysosomotropic agentssuch as chloroquine or ammonia to increase the lysosomal pH, theactivity of the proteases in the lysosomes is decreased, which proteasesappear to interact with at least certain antigenic moieties duringprocessing. It has also been found that the binding of antigen to classII MHC molecules is slow at neutral pH but is accelerated and enhancedin an acidic environment (Jensen, J. Exp. Med., 1990, 171:1779-1784). Inaddition, low lysosomal pH is a factor in regulating the recycling ofreceptor molecules in the vesicles, so that when the pH is raised, therate of recycling is reduced (Tietze et al., Biochen. Biophys. Res.Commun., 980, 93:1-8; Mellman et al., Ann. Rev. Biochem., 1986,55:663-700; Joshi et al., Cell Immunol., 1990, 125:518-525). Thisreduction of recycling could reduce the contact between class II MHCmolecules and antigen, resulting in fewer complexes being formed.

Lysosomes are small membrane-enclosed organelles which are found withinalmost all animal cells. Under normal conditions, lysosomes have aninternal pH in the range of 4.5 to 5. In contrast, the physiological pHoutside the cell is about 7.0. This difference can result in extensiveaccumulation within the lysosomes of weak bases. The weak bases canpermeate the cell and the lysosomal membranes in their unchargedmolecular form. However, the low ID internal pH of lysosomes favorsprotonation of the weak base molecules; once they are charged, themolecules are relatively membrane-impermeable and less able to pass backthrough the membrane. Such accumulation of weak bases will raise the pHin the lysosome (Maxfield, J. Cell Biol., 1982, 95:676-681; Ohkuma etal., Proc. Natl. Acad. Sci. USA, 1978, 75:3327-3331).

Other compounds, the ionophores, have also been shown to raise the pH inlysosomes (Maxfield, ibid.; Ohkuma et al., ibid.). The ionophoresincorporate in the lysosomal membranes and facilitate the exchange ofions, thereby destroying the normally-existing pH gradient (Pressman,"Alkali Metal Chelators--The Ionophores", in, Eichhorn, ed., InorganicBiochemistry, Vol. 1, pp. 218-221, Elsevier Scientific Publishing Co.,N.Y., 1973).

SUMMARY OF THE INVENTION

It is an object of the present invention to reduce or preventsensitization in a human patient caused by the transdermaladministration to the patient of a sensitizing drug.

This and other objects, features and advantages are met by the presentinvention which provides a method of reducing or preventing skinsensitization by inhibiting the immunological processing of asensitizing drug as an antigen. The drug is sensitizing to humans, i.e.,the drug is susceptible to inducing skin or mucosa sensitization in ahuman when the drug is transdermally administered to the human at atherapeutically effective rate. Skin sensitization reduction orprevention is induced by coadministering to the skin or mucosa of thehuman:

(a) a therapeutically effective amount of a sensitizing drug, at atherapeutically effective rate over a predetermined period of time; and

(b) an antigen processing-inhibiting agent in an amount effective toinhibit the processing of the drug as an antigen.

The system of the invention comprises a matrix adapted to be placed insensitizing drug and antigen processing-inhibiting agent transmittingrelation to the selected skin or mucosa site. The matrix containssufficient amounts of the drug and the agent to continuouslycoadminister to the skin or mucosa site the drug, at a therapeuticallyeffective rate and over a predetermined delivery period, and the antigenprocessing-inhibiting agent, at a rate and for a period of timesufficient to inhibit the processing of the drug as an antigen. A devicefor carrying out the invention may be either a passive transdermaldevice or an active transdermal device where transport of the agent isassisted by electric, sonic, thermal or other energy source.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of one embodiment of a transdermaltherapeutic device which may be used in accordance with the presentinvention.

FIG. 2 is a cross-sectional view of another embodiment of a transdermaltherapeutic device which may be used in accordance with the presentinvention.

FIG. 3 is a schematic view of an iontophoretic drug delivery devicewhich may be used in accordance with the present invention.

FIG. 4 illustrates graphically the reduction in elicitation ofsensitization to propranolol by coadministration of propranolol withammonium chloride.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, transdermal coadministration of asensitizing drug with an antigen processing-inhibiting agent reduces orprevents sensitization in humans by inhibiting the processing of thesensitizing drug as an antigen. This inhibition can take place at eitherthe induction phase or the elicitation phase of antigenic skinsensitization.

The present invention is applicable to any chemical agent or drug whichis normally delivered through body surfaces and membranes, includingskin and mucosa, and which tends to cause contact sensitivity or contactallergy to a human as a result of antigenic sensitization followingtransdermal application of the compound to the skin or mucosa. These arecompounds which are capable of being processed in and presented by theLangerhans or other cells as an antigen, resulting in sensitization ofthe T lymphocytes. As used herein, the expressions "drug" and "agent"are used interchangeably and are intended to have their broadestinterpretation as to any therapeutically active substance which isdelivered to a human to produce a desired, usually beneficial, effect.In general, this includes therapeutic agents in all of the majortherapeutic areas, including, but not limited to, anti-infectives suchas antibiotics and antiviral agents, analgesics and analgesiccombinations, anorexics, antiarthritics, antiasthmatic agents,anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,antihistamines, anti-inflammatory agents, antimigraine preparations,antimotion sickness preparations, antinauseants, antineoplastics,antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics,antispasmodics including gastrointestinal and urinary, anticholinergics,sympatholytics, sympathomimetrics, xanthine derivatives, cardiovascularpreparations including calcium channel blockers and beta-blockers,antiarrythmics, antihypertensives, diuretics, vasodilators includinggeneral, coronary, peripheral and cerebral, central nervous systemstimulants, cough and cold preparations, decongestants, diagnostics,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, psychostimulants, sedatives,tranquilizers, local anesthetics, opiate agonists, opiate antagonists,and pharmacologically active peptides, polypeptides and proteins.Examples of representative drugs within these classes include, by way ofexample and not for purposes of limitation, ketoprofen, piroxicam,indomethacin, scopolamine, imipramine, desipramine, nortriptyline,clemastine, chlorpheniramine, diphenhydramine, daunorubicin,chloroquine, quinacrine, chlorpromazine, fluphenazine, perphenazine,propranolol, alprenolol, betaxolol, labetalol, metoprolol, timolol,pindolol, atenolol, tetracaine, prilocaine, buprenorphine, naloxone,naltrexone, phentolamine, phenylpropanolamine, ephedrine, mephentermine,bitolterol, tolazoline, streptomycin, gentamycin, somatropin,somatotropin, somatostatin, insulin, insulin-like growth factor(somatomedins), luteinizing hormone releasing hormone, tissueplasminogen activator, and growth hormone releasing hormone.

Since a low pH, acidic intracellular environment appears to benecessary, or at least advantageous, to the processing and presentationof an antigen to cause a contact sensitization response in a human,those compositions that raise the intracellular pH of low pH organelles,and particularly the intralysosomal pH, of the Langerhans cells or otherantigen presenting cells of the skin would be effective as antigenprocessing-inhibiting agents.

The pH within the lysosomes can be raised in at least two differentways. The first is through the action upon lysosomal membranes by anagent that interferes with ion pumps and thereby allows theintralysosomal pH to rise, destroying the pH gradient and lessening thetendency to ionize compounds that may enter. Examples of suchinterfering agents are the ionophores, such as monensin,(R)(+)-1,1'-bi-2-naphthol, nigericin, valinomycin, gramicidin D, A23187,and carbonyl cyanide m-chlorophenylhydrazone. The second mode of actionis the uptake and accumulation of basic molecules and the resultingcompetition for available charge in the low pH lysosomalmicro-environment. These weak bases raise the pH within the lysosomes asthey accumulate. Examples of such weak base compounds are amphiphiliccations and include amphiphilic amines, such as ammonia and its salts(ammonium chloride being an example), low molecular weight amines (suchas methylamine, diethylamine and isopropylamine) and their salts, andaminoalcohols (such as ethanolamine, diethanolamine, triethanolamine andtromethamine) and their salts. In a presently preferred embodiment,accumulative weak base compounds, and particularly the amphiphilicamines, are preferred as the antigen processing-inhibiting agent.

The antigen processing-inhibiting agents can be selected from thoseexhibiting one or the other or both of the above two modes of action, orthey may be selected from other compounds that work by otherwise raisingthe intracellular, particularly the intralysosomal, pH or by mechanismsnot presently known. The basic requirement of an antigenprocessing-inhibiting agent under the present invention is that itinhibit the cellular pathway of antigen processing so that it inhibitsthe processing of a sensitizing drug or a biotransformation product of adrug as an antigen.

In this invention, the antigen processing-inhibiting agent iscontinuously and co-extensively administered with the sensitizing drugand to the same skin or mucosa as the drug in an amount sufficient toreduce or prevent sensitization by the drug in the human. For any givendrug and antigen processing-inhibiting agent combination, the amount canbe experimentally determined by those skilled in the art.

In one embodiment of the invention, the antigen processing-inhibitingagent should be coadministered with the drug throughout all or almostall of the time period during which the drug is administered. This isparticularly the case when the agent, once removed from the treatmentsite, quickly loses its inhibiting action; that is, once the agent isremoved, the internal pH within the lysosomes will begin to return toits normal lower level and as the pH lowers, the drug will begin to beprocessed as an antigen, causing sensitization in the patient. This isof particular concern when administration takes place over a relativelylong period of time, such as greater than 24 hours. In anotherembodiment of the invention, continuous coadministration of the drug andan antigen processing-inhibiting agent is not required when the agentcontinues to exert an action on the lysosomes for an extended periodafter it is removed from the treatment site. In such cases, the drug andthe agent are coadministered to a site for a sufficient period of timeto cause inhibition of the antigenic processing of the drug, after whichtime the drug alone may continue to be administered to the site.

In addition to coadministering the antigen processing-inhibiting agentduring administration of the drug, it is desirable in some instances topretreat the skin or mucosal administration site with the agent prior toapplication of the drug. This pretreatment will depend on the particularprocessing-inhibiting agent chosen as well as the drug to be used. Inthis manner, the lysosomal pH will have been sufficiently altered toinhibit antigen processing before the drug is present. Pretreatment withthe agent is especially useful when the agent is slow to affect thelysosomal pH or when the drug has a very rapid rate of entry into orprocessing within the lysosome.

According to the present invention, one or more antigenprocessing-inhibiting agents and the sensitizing drug are placed in drugand antigen processing-inhibiting agent transmitting relation with theappropriate body surface, preferably suspended in a carrier therefore,and maintained in place for the desired period of time. The drug andagent are typically dispersed within a physiologically compatible matrixor carrier which may be applied directly to the body as an ointment,gel, cream, suppository or sub lingual or buccal tablet, for example, orthey may be administered from a matrix or carrier in a transdermaltherapeutic delivery device or an iontophoretic delivery device.

The transdermal route of parenteral delivery of drugs provides manyadvantages, and transdermal therapeutic devices for delivering a widevariety of drugs or other beneficial agents are well known in the art.Typical devices are described in U.S. Pat. Nos. 3,598,122, 3,598,123,4,286,592, 4,314,557, 4,379,454, 4,559,222 and 4,573,995, for example,all of which are incorporated herein by reference. The coadministrationof an antigen processing-inhibiting agent and a sensitizing drug asdisclosed herein can be accomplished using transdermal devices of thesekinds.

In order to ensure co-extensive administration of drug and antigenprocessing-inhibiting agent to skin or mucosa, it is preferred toadminister the drug and agent from a matrix (e.g., a drug- andagent-containing matrix) in a transdermal delivery device, which matrixis placed in drug and antigen processing-inhibiting agent transmittingrelation with the skin or mucosa.

Two examples of suitable transdermal delivery devices are illustrated inFIGS. 1 and 2. In FIG. 1, transdermal delivery device 10 comprises areservoir 12 containing both a sensitizing drug and an antigenprocessing-inhibiting agent. Reservoir 12 is preferably in the form of amatrix containing the drug and agent dispersed therein. Reservoir 12 issandwiched between a backing layer 14, which is impermeable to both thedrug and the agent, and a rate-controlling membrane 16. In FIG. 1, thereservoir 12 is formed of a material, such as a rubbery polymer, that issufficiently viscous to maintain its shape. If a lower viscositymaterial is used for reservoir 12, such as an aqueous gel, backing layer14 and rate-controlling membrane 16 would be sealed together about theirperiphery to prevent leakage. The device 10 adheres to the surface ofthe skin 20 by means of an in-line contact adhesive layer 18. Theadhesive layer 18 may optionally contain agent and/or drug. A strippablerelease liner (not shown) is normally provided along the exposed surfaceof adhesive layer 18 and is removed prior to application of device 10 tothe skin 20.

Alternatively, as shown in FIG. 2, transdermal therapeutic device 22 maybe attached to the skin or mucosa of a patient by means of an adhesiveoverlay 28. Device 22 is comprised of a drug- and agent-containingreservoir 24 which is preferably in the form of a matrix containing thedrug and the agent dispersed herein. An impermeable backing layer 26 isprovided adjacent one surface of reservoir 24. Adhesive overlay 28maintains the device on the skin and may be fabricated together with, orprovided separately from, the remaining elements of the device. Withcertain formulations, the adhesive overlay 28 may be preferable to thein-line contact adhesive 18 as shown in FIG. 1. This is true, forexample, where the drug/agent reservoir contains a material (such as,for example, an oily surfactant permeation enhancer) which adverselyaffects the adhesive properties of the in-line contact adhesive layer18. Impermeable backing layer 26 is preferably slightly larger thanreservoir 24, and in this manner prevents the materials in reservoir 24from adversely interacting with the adhesive in overlay 28. Optionally,a rate-controlling membrane (not shown in FIG. 2) similar to membrane 16in FIG. 1 may be provided on the skin/mucosa side of reservoir 24. Astrippable release liner 30 is also provided with device 22 and isremoved just prior to application of device 22 to the skin.

In those cases where it is desired to pretreat the skin or mucosa withthe antigen processing-inhibiting agent prior to coadministration ofdrug/agent or where the drug flux is much greater than the agent flux,an amount of the agent may be present in the adhesive layer 18. On theother hand, where it is not necessary to pretreat the application siteor where there is no great disparity between drug and agent fluxes, boththe drug and the agent may be delivered from the adhesive layer 18 aswell as from the reservoir 24. The drug and the antigenprocessing-inhibiting agent can be co-extensively administered to humanskin or mucosa by direct application to the skin or mucosa in the formof an ointment, gel, cream or lotion, for example, but is preferablyadministered from a skin patch or other known transdermal deliverydevice which contains a saturated or unsaturated formulation of the drugand the agent. The formulation may be aqueous or non-aqueous based. Theformulation should be designed to deliver the sensitizing drug and theantigen processing-inhibiting agent at the necessary fluxes. Dependingon the drug to be delivered, the drug and agent carrier(s) may be eitheraqueous or non-aqueous based. Aqueous formulations typically comprisewater and about 1-2 weight % of a hydrophilic polymer as a gellingagent, such as hydroxyethylcellulose or hydroxypropylcellulose. Typicalnon-aqueous gels are comprised of silicone fluid or mineral oil. Mineraloil-based gels also typically contain 1-2 weight % of a gelling agentsuch as colloidal silicon dioxide. The suitability of a particular geldepends upon the compatibility of its constituents with both thesensitizing drug and the antigen processing-inhibiting agent, along witha permeation enhancer, if one is present, and any other components inthe formulation.

The reservoir matrix should be compatible with the drug, the antigenprocessing-inhibiting agent and any carrier therefor. When using anaqueous-based system, the reservoir matrix is preferably a hydrophilicpolymer, e.g., a hydrogel. When using a non-aqueous-based system, thereservoir matrix is preferably composed of a hydrophobic polymer.Suitable polymeric matrices are well known in the transdermal drugdelivery art, and examples are listed in the above-named patentspreviously incorporated herein by reference.

When a constant drug delivery rate is desired, the sensitizing drug ispresent in the matrix or carrier at a concentration in excess ofsaturation, the amount of excess being a function of the desired lengthof the drug delivery period of the system. The drug may, however, bepresent at a level below saturation without departing from thisinvention as long as the drug and the antigen processing-inhibitingagent are continuously and co-extensively administered to the same skinor mucosa site in an amount and for a period of time sufficient toreduce or eliminate skin sensitization by the drug.

In addition to the sensitizing drug and the antigenprocessing-inhibiting agent, which are essential to the invention, thematrix or carrier may also contain dyes, pigments, inert fillers,permeation enhancers (for either the drug or the inhibiting agent or forboth), excipients and other conventional components of pharmaceuticalproducts or transdermal devices known to the art.

Drugs may also be delivered transdermally by iontophoresis, andiontophoretic devices for delivering a wide variety of drugs or otherbeneficial agents are well known in the art. Iontophoretic deliverydevices include a donor electrode assembly which includes a donorelectrode and a reservoir containing the beneficial agent to beiontophoretically delivered. The donor electrode assembly is adapted tobe placed in agent transmitting relation with the skin or mucosa of thepatient. The device also includes a counter electrode assembly adaptedto be placed in electrical contact with the skin at a location spacedapart from the donor electrode. Further, the device includes an electricpower source. The electrodes and the power source are electricallyconnected and form a closed circuit when the electrode assemblies areplaced in current conducting relation with the skin of the patient. Thecoadministration of an antigen processing-inhibiting agent and asensitizing drug as disclosed herein can be accomplished using anyiontophoretic device. Typical devices are described in U.S. Pat. Nos.3,991,755, 4,141,359, 4,250,878, 4,274,420, 4,325,367, 4,391,278,4,398,545, 4,419,092, 4,474,570, 4,557,723, 4,640,689, 4,702,732 and4,708,716, for example, all of which are incorporated herein byreference.

FIG. 3 illustrates one example of a preferred iontophoretic deliverydevice 40. Device 40 has a top layer 41 which contains an electricalpower supply (e.g., a battery or a series of batteries) as well asoptional control circuitry such as a current controller (e.g., aresistor or a transistor-based current control circuit), an on/offswitch, and/or a microprocessor adapted to control the current output ofthe power source over time. Device 40 also includes electrode assembly51 and electrode assembly 53. Electrode assemblies 51 and 53 areseparated from one another by an electrical insulator 46 and formtherewith a single self-contained unit. For purposes of illustration,the electrode assembly 51 will be referred to as the "donor" electrodeassembly while electrode assembly 53 will be referred to as the"counter" electrode assembly. In this embodiment, the donor electrode 42is positioned adjacent drug reservoir 44 while the counter electrode 43is positioned adjacent the return reservoir 45 which contains anelectrolyte. Electrodes 42 and 43 are formed from metal foils (such assilver or zinc) or a polymer matrix loaded with metal powder, powderedgraphite, carbon fibers or any other suitable electrically conductivematerial. Reservoirs 44 and 45 can be polymeric matrices or gelmatrices. Insulator 46 is composed of a non-electrical conducting andnon-ion-conducting material which acts as a barrier to preventshort-circuiting of the device 40. Insulator 46 can be an air gap, anon-ion-conducting polymer or adhesive or other suitable barrier to ionflow. The device 40 is adhered to the skin by means of ion-conductingadhesive layers 47 and 48. The device 40 also includes a strippablerelease liner 49 which is removed just prior to application to the skin.

In a typical device 40, the drug reservoir 44 contains an ionizablesupply of the drug to be delivered together with the antigenprocessing-inhibiting agent, and the counter reservoir 45 contains asuitable electrolyte. In this way, the positive drug ions are deliveredthrough the skin from the anode electrode assembly. The drug reservoir44 of the iontophoretic delivery device 40 must be in drug andprocessing-inhibiting agent relation with the skin or mucosa. It is notnecessary, however, that the return reservoir 45 be in electrolytetransmitting relation with the skin or mucosa, although this ispreferred. It has been found to be preferable to use a water-solublesalt of the drug or agent to be delivered.

In the present invention, the drug is delivered at a therapeuticallyeffective rate and the agent is delivered at an antigenprocessing-inhibiting rate for a predetermined time period. The relevanttime frame varies with the regimen of drug administration involved. Somedrugs must be administered continuously for one or more days. In thatinstance, a suitable transdermal device would have sufficient drug andantigen processing inhibitor to provide the necessary rate of deliveryof up to 24 hours for devices that are replaced periodically or of up toa week for longer-duration devices. Some drugs are only administeredonce and in that instance, a suitable device would have sufficient drugand antigen processing inhibitor to provide the necessary rates ofdelivery for a few hours.

The minimum required administration amount and rate of the antigenprocessing-inhibiting agent in the present invention depends upon anumber of factors including the type and amount of sensitizing drugbeing administered, the period of time over which the drug and the agentare coadministered, the type of action exhibited by the agent (forexample, whether it lowers lysosomal pH by interference or accumulationaction), and the potency of the agent. Typically, all other variablesbeing equal, the concentrations of accumulative weak base compounds thatare required will be higher than the concentrations of ionophores, sincetheir mechanism of action is by accumulation. Thus, the amount of weakbase antigen processing-inhibiting agent required to inhibit theprocessing of a drug as an antigen in the lysosomes is from about 0.2wt% (weight percent) to about 20 wt% of the drug/agent composition,whereas the amount of ionophore antigen processing-inhibiting agentrequired is from about 0.01 wt% to about 5 wt%.

The following examples are offered to illustrate the practice of thepresent invention. It is important to note that this invention is notlimited to any particular transdermal device or other form oftransdermal delivery, as are commonly known in the art. Nor is thisinvention limited to a particular formulation. Therefore, theembodiments described herein are merely illustrative and are notintended to limit the scope of the invention in any manner.

EXAMPLE 1

Reduction of the elicitation phase of sensitization to propranolol, Badrenergic blocker, was demonstrated as follows.

Hydroxyethylcellulose gels buffered to pH 8 and containing 0.5 wt%propranolol and 0, 2, 4, or 8 wt% ammonium chloride were formulated.Twenty microliters of each preparation was applied in duplicate underocclusion for 3 hours on the arm of a human subject known to besensitized to propranolol. Skin reactions which occurred were evaluatedusing a Minolta Chromameter. Reaction to propranolol alone reached amaximum at seven days. At this time, a partial inhibition of theelicitation reaction was obtained with all of the ammonium chlorideconcentrations, and 90% inhibition of the reaction was obtained with 4wt% of ammonium chloride (see FIG. 4).

EXAMPLE 2

Reduction of the elicitation phase of sensitization to tetracaine wasdemonstrated as follows.

Hydroxyethylcellulose gels buffered to pH 8 and containing 2.0 wt%tetracaine and 0, 2, 4, or 8 wt% ammonium chloride were formulated.Twenty microliters of each preparation was applied in duplicate underocclusion for 3 hours on the arm of a human subject known to besensitized to tetracaine. Twenty-one hours later, the reactions wereevaluated using a Minolta Chromameter. A partial inhibition of theelicitation reaction was obtained with all of the ammonium chlorideconcentrations.

EXAMPLE 3

Hydroxyethylcellulose gels buffered to pH 8.0 and containing 1.0%propranolol and 4 wt% ammonium chloride (gel A) or 1.0% propranololalone (gel B) are formulated.

Gels are applied to two groups of human subjects. Individuals in group Areceive 100 ll of gel A in an aluminum "Finn cup". The application isoccluded and left in place for 16 hours. Applications are repeated suchthat nine applications are spaced out over a three-week period, eachapplication being to a different site on the subject. Subjects in GroupB receive gel B which contains propranolol but no ammonium chloride. Thegel is applied in the same manner and over the same time period as ingroup A.

Two weeks after the ninth application is removed, all subjects from bothgroups receive a 16 hour application of a hydroxyethylcellulose gelbuffered to pH 8.0 and containing 0.1% propranolol (the "challenge"application). Following removal, the site of application is observed andscored for erythema, induration and edema at 2 hr, 24 hr, 48 hr and 72hr.

In the ten subjects of group A, the site of application shows a slighterythema at the 2 hr reading which progressively decreases in intensity,being only barely perceptible at 24 hr and disappearing by 48 hr. Thisreaction is typical of minor irritation and indicates that the subjectsdid not become sensitized to propranolol.

In eight of the ten subjects in group B, the site of challenge shows aslight erythema at 2 hr, which progressively increases in intensity toreach a peak by 48 hr. In addition, the sites become raised (edematous)and palpable (indurated). In the remaining two subjects of group B, theslight erythema seen at the 2 hr reading progressively decreases, beingonly slightly perceptible at 24 hr and disappearing by 48 hr. Thus,eight of the subjects are sensitized to propranolol, and two show minorirritation.

The invention reduces the incidence of sensitization to propranolol from80% to 0%.

While this invention has been described in detail with particularreference to certain preferred embodiments thereof, it will beunderstood that variations and modifications can be effected withoutdeparting from the spirit and scope of the invention as defined in theappended claims.

What is claimed is:
 1. A method of reducing or preventing human skinsensitization during transdermal administration to a human of asensitizing drug, which drug is susceptible to inducing skinsensitization in the human when the drug is transdermally administered,the method comprising coadministering to a selected site on the skin ormucosa of the human:(a) a therapeutically effective amount of thesensitizing drug, at a therapeutically effective rate over apredetermined period of time, wherein the drug is selected fromketoprofen, piroxicam, indomethacin, scopolamine, imipramine,desipramine, nortriptyline, clemastine, chlorpheniramine,diphenhydramine, daunorubicin, chloroquine, quinacrine, chlorpromazine,fluphenazine, perphenazine, propranolol, alprenolol, betaxolol,labetalol, metoprolol, timolol, pindolol, atenolol, tetracaine,prilocaine, buprenorphine, naloxone, naltrexone, phentolamine,phenylpropanolamine, ephedrine, mephentermine, bitolterol, tolazoline,streptomycin, gentamycin, somatropin, somatotropin, somatostatin,insulin, insulin-like growth factor (somatomedins), luteinizing hormonereleasing hormone, tissue plasminogen activator, and growth hormonereleasing hormone; and (b) an antigen processing-inhibiting agent in anamount effective to inhibit the processing of the drug as an antigen,wherein the agent is either an ionophore, in an amount of from about0.01 wt% to about 5 wt%, or an amphiphilic amine, in an amount of fromabout 0.2 wt% to about 20 wt%.
 2. A method according to claim 1 whereinthe drug and the agent are coadministered transdermally from a matrixplaced in drug and agent transmitting relation with the skin or mucosa.3. A method of reducing or preventing the elicitation of human skinsensitization during transdermal administration to a human of asensitizing drug to which the human is sensitized, which drug issusceptible to inducing skin sensitization in the human when the drug istransdermally administered, the method comprising coadministering to aselected site on the skin or mucosa of the human:(a) a therapeuticallyeffective amount of the sensitizing drug, at a therapeutically effectiverate over a predetermined period of time, wherein the drug is selectedfrom ketoprofen, piroxicam, indomethacin, scopolamine, imipramine,desipramine, nortriptyline, clemastine, chlorpheniramine,diphenhydramine, daunorubicin, chloroquine, quinacrine, chlorpromazine,fluphenazine, perphenazine, propranolol, alprenolol, betaxolol,labetalol, metoprolol, timolol, pindolol, atenolol, tetracaine,prilocaine, buprenorphine, naloxone, naltrexone, phentolamine,phenylpropanolamine, ephedrine, mephentermine, bitolterol, tolazoline,streptomycin, gentamycin, somatropin, somatotropin, somatostatin,insulin, insulin-like growth factor (somatomedins), luteinizing hormonereleasing hormone, tissue plasminogen activator, and growth hormonereleasing hormone; and (b) an antigen processing-inhibiting agent in anamount effective to inhibit the processing of the drug as an antigen,wherein the agent is either an ionophore, in an amount of from about0.01 wt% to about 5 wt%, or an amphiphilic amine, in an amount of fromabout 0.2 wt% to about 20 wt%.
 4. A method according to claim 3 whereinthe drug and the agent are coadministered transdermally from a matrixplaced in drug and agent transmitting relation with the skin or mucosa.5. A method according to claim 3 wherein the drug is propranolol and theagent is ammonium chloride.
 6. A method according to claim 3 wherein thedrug is tetracaine and the agent is ammonium chloride.
 7. A method ofreducing or preventing the induction of human skin sensitization duringtransdermal administration to a human of a sensitizing drug, which drugis susceptible to inducing skin sensitization in the human when the drugis transdermally administered, the method comprising coadministering toa selected site on the skin or mucosa of the human:(a) a therapeuticallyeffective amount of the sensitizing drug, at a therapeutically effectiverate over a predetermined period of time, wherein the drug is selectedfrom ketoprofen, piroxicam, indomethacin, scopolamine, imipramine,desipramine, nortriptyline, clemastine, chlorpheniramine,diphenhydramine, daunorubicin, chloroquine, quinacrine, chlorpromazine,fluphenazine, perphenazine, propranolol, alprenolol, betaxolol,labetalol, metoprolol, timolol, pindolol, atenolol, tetracaine,prilocaine, buprenorphine, naloxone, naltrexone, phentolamine,phenylpropanolamine, ephedrine, mephentermine, bitolterol, tolazoline,streptomycin, gentamycin, somatropin, somatotropin, somatostatin,insulin, insulin-like growth factor (somatomedins), luteinizing hormonereleasing hormone, tissue plasminogen activator, and growth hormonereleasing hormone; and (b) an antigen processing-inhibiting agent in anamount effective to inhibit the processing of the drug as an antigen,wherein the agent is either an ionophore, in an amount of from about0.01 wt% to about 5 wt%, or an amphiphilic amine, in an amount of fromabout 0.2 wt% to about 20 wt%.
 8. A method according to claim 7 whereinthe drug and the agent are coadministered transdermally from a matrixplaced in drug and agent transmitting relation with the skin or mucosa.9. A transdermal drug delivery device for transdermally administering asensitizing drug to a human, which drug is susceptible to inducing skinor mucosal sensitization in the human when the drug is transdermallydelivered, the device comprising:(a) a matrix adapted to be placed indrug and antigen processing-inhibiting agent transmitting relation witha selected site on the skin or mucosa of the human, the matrixcontaining sufficient amounts of drug and antigen processing-inhibitingagent to continuously and co-extensively administer to the skin ormucosal site: (1) a therapeutically effective amount of the sensitizingdrug, at a therapeutically effective rate over a predetermined period oftime, wherein the drug is selected from ketoprofen, piroxicam,indomethacin, scopolamine, imipramine, desipramine, nortriptyline,clemastine, chlorpheniramine, diphenhydramine, daunorubicin,chloroquine, quinacrine, chlorpromazine, fluphenazine, perphenazine,propranolol, alprenolol, betaxolol, labetalol, metoprolol, timolol,pindolol, atenolol, tetracaine, prilocaine, buprenorphine, naloxone,naltrexone, phentolamine, phenylpropanolamine, ephedrine, mephentermine,bitolterol, tolazoline, streptomycin, gentamycin, somatropin,somatotropin, somatostatin, insulin, insulin-like growth factor(somatomedins), luteinizing hormone releasing hormone, tissueplasminogen activator, and growth hormone releasing hormone; and (2) anantigen processing-inhibiting amount of the antigenprocessing-inhibiting agent capable of inhibiting processing of the drugas an antigent to reduce or prevent sensitization to the skin or mucosa,wherein the agent is either an ionophore, in an amount of from about0.01 wt% to about 5 wt %, or an amphiphilic amine, in an amount of fromabout 0.2 wt% to about 20 wt %.
 10. A method according to claim 1wherein the drug is propranolol and the agent is ammonium chloride. 11.A method according to claim 1 wherein the drug is tetracaine and theagent is ammonium chloride.
 12. A device according to claim 9 whereinthe drug is propranolol and the agent is ammonium chloride.
 13. A deviceaccording to claim 9 wherein the drug is tetracaine and the agent isammonium chloride.